Respiratory syncytial virus replication inhibitors

ABSTRACT

This invention concerns compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     prodrugs, addition salts, or stereochemically isomeric forms thereof for use as, inter alia, respiratory syncytial virus replication inhibitors; their preparation, compositions containing them and methods of their use in treating respiratory syncytial viral infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a divisional application of U.S. application Ser.No. 10/817,472, filed Apr. 2, 2004 (now allowed), which is a divisionalapplication of U.S. application Ser. No. 10/019,380, filed Dec. 27,2001, now U.S. Pat. No. 6,747,028, which is the national stage entryunder 35 U.S.C. § 371 of PCT/EP00/05675, filed Jun. 20, 2000 in English,which claims priority to EPO 99202088.3, filed Jun. 28, 1999, thedisclosures of which are incorporated herein by reference in theirentirety.

The present invention is concerned with benzimidazoles andimidazopyridines having antiviral activity, in particular, they have aninhibitory activity on the replication of the respiratory syncytialvirus. It further concerns their preparation and compositions comprisingthem, as well as their use as a medicine.

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumovirinae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.Ribavirin, a nucleoside analogue, provides an aerosol treatment forserious RSV infection in hospitalized children. The aerosol route ofadministration, the toxicity (risk of teratogenicity), the cost and thehighly variable efficacy limit its use. The other two drugs, RespiGam®and palivizumab, polyclonal and monoclonal antibody immunostimulants,are intended to be used in a preventive way.

Other attempts to develop a safe and effective RSV vaccine have all metwith failure thus far. Inactivated vaccines failed to protect againstdisease, and in fact in some cases enhanced disease during subsequentinfection. Life attenuated vaccines have been tried with limitedsuccess. Clearly there is a need for an efficacious non-toxic and easyto administer drug against RSV replication.

EP-A-0,005,138, EP-A-0,099,139, EP-A-0,145,037, EP-A-0,144,101,EP-A-0,151,826, EP-A-0,151,824, EP-A-0,232,937, EP-A-0,295,742, EP0,297,661, EP-A-0,307,014, WO 92 01697 describe benzimidazole andimidazopyridine substituted piperidine and piperazine derivatives asantihistaminics, antiallergics or serotonine antagonists.

The present invention concerns the compounds of formula (I)

their prodrugs, N-oxides, addition salts, quaternary amines, metalcomplexes and stereochemically isomeric forms wherein

-   -a¹=a²-a³=a⁴-represents a bivalent radical of formula    —CH═CH—CH═CH—  (a-1);    —N═CH—CH═CH—  (a-2);    —CH═N—CH═CH—  (a-3);    —CH═CH—N═CH—  (a-4); or    —CH═CH—CH═N—  (a-5);    -   wherein each hydrogen atom in the radicals (a-1), (a-2), (a-3),        (a-4) and (a-5) may optionally be replaced by halo, C₁₋₆alkyl,        nitro, amino, hydroxy, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl,        carboxyl, aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,        C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl, or a radical of formula

-   -    wherein =Z is ═O, ═CH—C(═O)—NR^(5a)R^(5b), ═CH₂, ═CH—C₁₋₆alkyl,        ═N—OH or ═N—O—C₁₋₆alkyl;

-   Q is a radical of formula

wherein Alk is C₁₋₆alkanediyl;

-   -   Y¹ is a bivalent radical of formula —NR²— or —CH(NR²R⁴)—;    -   X¹ is NR⁴, S, S(═O), S(═O)₂, O, CH₂, C(═O), C(═CH₂), CH(OH),        CH(CH₃), CH(OCH₃), CH(SCH₃), CH(NR^(5a)R^(5b)), CH₂—NR⁴ or        NR⁴—CH₂;    -   X² is a direct bond, CH₂, C(═O), NR⁴, C₁₋₄alkyl-NR⁴,        NR⁴—C₁₋₄alkyl;    -   t is 2, 3, 4 or 5;    -   u is 1, 2, 3, 4 or 5;    -   v is 2 or 3; and

-   whereby each hydrogen atom in Alk and the carbocycles and the    heterocycles defined in radicals (b-3), (b-4), (b-5), (b-6), (b-7)    and (b-8) may optionally be replaced by R³; with the proviso that    when R³ is hydroxy or C₁₋₆alkyloxy, then R³ can not replace a    hydrogen atom in the α position relative to a nitrogen atom;

-   G is C₁₋₁₀alkanediyl substituted with one or more hydroxy,    C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, C₁₋₆alkylthio, arylC₁₋₆alkylthio,    HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— or    arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—;

-   R¹ is a monocyclic heterocycle or aryl; said heterocycle being    selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl,    pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl,    pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl,    isoxazolyl, oxadiazolyl; and each heterocycle may optionally be    substituted with 1 or where possible more, such as 2, 3 or 4,    substituents selected from halo, hydroxy, amino, cyano, carboxy,    C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, aryl,    arylC₁₋₆alkyl, arylC₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, mono- or    di(C₁₋₆alkyl)amino, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,    polyhaloC₁₋₆alkyl, C₁₋₆alkylcarbonylamino, C₁₋₆alkyl-SO₂—NR^(5c)—,    aryl-SO₂—NR^(5c)—, C₁₋₆alkyloxycarbonyl, —C(═O)—NR^(5c)R^(5d),    HO(—CH₂—CH₂—O)_(n)—, halo(—CH₂—CH₂—O)_(n)—,    C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— and    mono- or di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—;

-   each n independently is 1, 2, 3 or 4;

-   R² is hydrogen, formyl, C₁₋₆alkylcarbonyl, Hetcarbonyl,    pyrrolidinyl, piperidinyl, homopiperidinyl, C₃₋₇cycloalkyl    substituted with N(R⁶)₂, or C₁₋₁₀alkyl substituted with N(R⁶)₂ and    optionally with a second, third or fourth substituent selected from    amino, hydroxy, C₃₋₇cycloalkyl, C₂₋₅alkanediyl, piperidinyl, mono-    or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, aryl and aryloxy;

-   R³ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, arylC₁₋₆alkyl or    arylC₁₋₆alkyloxy;

-   R⁴ is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl;

-   R^(5a), R^(5b), R^(5c) and R^(5d) each independently are hydrogen or    C₁₋₆alkyl; or

-   R^(5a) and R^(5b), or R^(5c) and R^(5d) taken together form a    bivalent radical of formula —(CH₂)_(s)— wherein s is 4 or 5;

-   R⁶ is hydrogen, C₁₋₄alkyl, formyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkylcarbonyl or C₁₋₆alkyloxycarbonyl;

-   aryl is phenyl or phenyl substituted with 1 or more, such as 2, 3 or    4, substituents selected from halo, hydroxy, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, and C₁₋₆alkyloxy;

-   Het is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.

The term prodrug as used throughout this text means thepharmacologically acceptable derivatives, e.g. esters and amides, suchthat the resulting biotransformation product of the derivative is theactive drug as defined in the compounds of formula (I). The reference byGoodman and Gilman (The Pharmacological Basis of Therapeutics, 8^(th)ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15)describing prodrugs generally, is hereby incorporated.

As used herein C₁₋₃alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 3carbon atoms such as methyl, ethyl, propyl, 1-methylethyl and the like;C₁₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as the group defined for C₁₋₃alkyl and butyl and the like;C₂₋₄alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 2 to 4 carbon atomssuch as ethyl, propyl, 1-methylethyl, butyl and the like; C₁₋₆alkyl as agroup or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 6 carbon atoms such as the groupsdefined for C₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like;C₁₋₉alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 9 carbon atomssuch as the groups defined for C₁₋₆alkyl and heptyl, octyl, nonyl,2-methylhexyl, 2-methylheptyl and the like; C₁₋₁₀alkyl as a group orpart of a group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 10 carbon atoms such as the groups defined forC₁₋₉alkyl and decyl, 2-methylnonyl and the like. C₃₋₇cycloalkyl isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; C₂₋₅alkanediyl defines bivalent straight and branched chainsaturated hydrocarbon radicals having from 2 to 5 carbon atoms such as,for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like,C₂₋₅alkanediyl is substituted on C₁₋₁₀alkyl as provided for in thedefinition of R², it is meant to be substituted on one carbon atom thusforming a spiro moiety; C₁₋₄alkanediyl defines bivalent straight andbranched chain saturated hydrocarbon radicals having from 1 to 4 carbonatoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl and the like; C₁₋₆alkanediyl is meant to includeC₁₋₄alkanediyl and the higher homologues thereof having from 5 to 6carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl andthe like; C₁₋₁₀alkanediyl is meant to include C₁₋₆alkanediyl and thehigher homologues thereof having from 7 to 10 carbon atoms such as, forexample, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl,1,10-decanediyl and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. The term (═N—OH) forms a hydroxylimine moiety when attachedto a carbon atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as mono- or polyhalosubstituted C₁₋₆alkyl, inparticular methyl with one or more fluoro atoms, for example,difluoromethyl or trifluoromethyl. In case more than one halogen atomsare attached to an alkyl group within the definition ofpolyhaloC₁₋₄alkyl, they may be the same or different.

When any variable (e.g. aryl, R², R³, R⁴, R^(5a), R^(5b) etc.) occursmore than one time in any constituent, each definition is independent.

It will be appreciated that some of the compounds of formula (I) andtheir prodrugs, N-oxides, addition salts, quaternary amines, metalcomplexes and stereochemically isomeric forms may contain one or morecenters of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their prodrugs, N-oxides, addition salts, quaternary amines,metal complexes or physiologically functional derivatives may possess.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereo-chemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure as well as each of the individual isomericforms of formula (I) and their prodrugs, N-oxides, salts, solvates orquaternary amines substantially free, i.e. associated with less than10%, preferably less than 5%, in particular less than 2% and mostpreferably less than 1% of the other isomers. Stereochemically isomericforms of the compounds of formula (I) are obviously intended to beembraced within the scope of this invention. As used hereinafter theterms R or S are well-known by the person skilled in the art

For some of the compounds of formula (I), their prodrugs, N-oxides,salts, solvates, quaternary amines, or metal complexes and theintermediates used in the preparation thereof, the absolutestereochemical configuration was not experimentally determined. In thesecases the stereoisomeric form which was first isolated is designated as“A” and the second as “B”, without further reference to the actualstereochemical configuration. However, said “A” and “B” stereoisomericforms can be unambiguously characterized by for instance their opticalrotation in case “A” and “B” have an enantiomeric relationship. A personskilled in the art is able to determine the absolute configuration ofsuch compounds using art-known methods such as, for example, X-raydiffraction. In case “A” and “B” are stereoisomeric mixtures, they canbe further separated whereby the respective first fractions isolated aredesignated “A1” and “B1” and the second as “A2” and “B2”, withoutfurther reference to the actual stereochemical configuration.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioicacid), tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

It will be appreciated that the compounds of formula (I) may have metalbinding, chelating, complexating properties and therefore may exist asmetal complexes or metal chelates. Such metalated derivatives of thecompounds of formula (I) are intended to be included within the scope ofthe present invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

A special group of corn pounds are those compounds of formula (I)wherein one or more of the following restrictions apply:

-   -   Q is a radical of formula (b-1), (b-3), (b-4), (b-5), (b-6),        (b-7) or (b-8);    -   X² is a direct bond, CH₂ or C(═O);    -   R² is hydrogen, pyrrolidinyl, piperidinyl, homopiperidinyl,        C₃₋₇cycloalkyl substituted with NHR⁶, or C₁₋₁₀alkyl substituted        with NHR⁶ and optionally with a second, third or fourth        substituent selected from amino, hydroxy, C₃₋₇cycloalkyl,        C₂₋₅alkanediyl, piperidinyl, mono- or di(C₁₋₆alkyl)amino,        C₁₋₆alkyloxycarbonylamino, aryl and aryloxy;    -   R³ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy or        arylC₁₋₆alkyl;    -   R⁶ is hydrogen, C₁₋₄alkyl, formyl, C₁₋₆alkylcarbonyl or        C₁₋₆alkyloxycarbonyl.

Also an interesting group of compounds are those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -a¹=a²-a³=a⁴- is a radical of formula (a-1) or (a-2);-   R¹ is phenyl optionally substituted with halo, C₁₋₆alkyl or    C₁₋₄alkyloxy; or pyridyl optionally substituted with 1 or more    substituents selected from arylC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyl,    aryl, mono- or di(C₁₋₆alkyl)amino, C(═O)—NR^(5c)R^(5d), halo or    C₁₋₆alkyl;-   G is C₁₋₄alkanediyl substituted with hydroxy, C₁₋₆alkyloxy,    HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— or    arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—;-   Q is a radical of formula (b-5) wherein v is 2, and Y¹ is N—R²;-   X¹ is NH or CH₂;-   R² is hydrogen or C₁₋₁₀alkyl susbstituted with NHR⁶ wherein R⁶ is    hydrogen or C₁₋₆alkyloxycarbonyl.

Particular compounds are those compounds of formula (I) wherein R² isC₁₋₁₀alkyl substituted with NH₂.

Other particular compounds are those compounds of formula (I) wherein Gis methylene or 1,2-ethanediyl, both substituted with hydroxy,C₁₋₆alkyloxy, HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— orarylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—.

Also particular compounds are those compounds of formula (I) wherein R¹is pyridyl, preferably 2-pyridyl, substituted with one or 2 substituentsselected from halo, hydroxy, amino, cyano, carboxy, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)amino, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, polyhaloC₁₋₆alkyl,C₁₋₆alkylcarbonylamino, C₁₋₆alkyl-SO₂—NR^(5c)—, aryl-SO₂—NR^(5c)—,C₁₋₆alkyloxycarbonyl, —C(═O)—NR^(5c)R^(5d), HO(—CH₂—CH₂—O)_(n)—,halo(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—,arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— and mono- ordi(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—, preferably selected fromarylC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyl, aryl, mono- ordi(C₁₋₆alkyl)amino, C(═O)—NR^(5a)R^(5b), halo or C₁₋₆alkyl.

Preferred compounds are those compounds of formula (I) wherein R¹ is anoptionally substituted 2-pyridyl moiety, in particular, a 2-pyridyl, a6-substituted-2-pyridyl or a 3,6-disubstituted-2-pyridyl moiety.

Preferred compounds are

-   [(A),(S)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)-ethoxymethyl]-1H-benzimidazol-2-amine    (compound 69);-   [(A),(S)]-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    (compound 75);-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    (compound 86);-   N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-6-chloro-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-4-methyl-1H-benzimidazol-2-amine    trihydrochloride trihydrate (compound 88);-   [(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    monohydrate (compound 68);-   (±)-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    (compound 12);-   [(A)(S)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    monohydrate (compound 67);-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1-H-benzimidazol-2-amine    (compound 83);-   [(A),(R)]-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    monohydrate (compound 74);-   (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-2-benzimidazol-2-amine    (compound 9);-   (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    (compound 64);-   [(B),(S)]N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    monohydrate (compound 76);-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-3-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)methyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine    (compound 89);-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-phenyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine    (compound 85);-   (±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-methoxyethoxy)(6-methyl-2-pyridinyl)-methyl]-1H-benzimidazol-2-amine    (compound 82);-   the prodrugs, N-oxides, addition salts, quaternary amines, metal    complexes and stereochemically isomeric forms thereof.

Most preferred are

-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-4-methyl-1H-benzimidazol-2-amine    monohydrate (compound 87);-   [(A),(R)]-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine    (compound 70);-   (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine    (compound 10);-   the prodrugs, N-oxides, addition salts, quaternary amines, metal    complexes and stereochemically isomeric forms thereof.

In general, compounds of formula (I) can be prepared by reacting anintermediate of formula (II-a) or (II-b), wherein P represents aprotecting group, such as, for example C₁₋₄alkyloxycarbonyl, or thoseprotecting groups mentioned in Chapter 7 of ‘Protective Groups inOrganic Synthesis’ by T Greene and P. Wuyts (John Wiley & Sons Inc.,1991), with an intermediate of formula (III), wherein W₁ is a suitableleaving group, such as a halo atom, e.g. chloro, bromo, in the presenceof a suitable base, such as, e.g. sodium hydride. Said reaction can beperformed in a reaction-inert solvent, such as N,N-dimethylformamide.

Compounds of formula (I) wherein, in the definition of Q, R² or at leastone R⁶ substituent is hydrogen, said Q being represented by H-Q₁, andsaid compounds being represented by formula (I-a), can be prepared bydeprotecting an intermediate of formula (IV) wherein P represents aprotecting group, for example C₁₋₄alkyloxycarbonyl, benzyl, or thoseprotecting groups mentioned in Chapter 7 of ‘Protective Groups inOrganic Synthesis’ by T Greene and P. Wuyts (John Wiley & Sons Inc.,1991).

When P represents, for example, C₁₋₄alkyloxycarbonyl, said deprotectionreaction can be performed by, for example, acidic hydrolysis in thepresence of a suitable acid, such as hydrobromic, hydrochloric,sulfuric, acetic, or trifluoroacetic acid or a mixture of said acids, orby alkaline hydrolysis in the presence of a suitable base, such as, forexample potassium hydroxide, in a suitable solvent such as water,alcohol, a mixture of water-alcohol, methylene chloride. Suitablealcohols are methanol, ethanol, 2-propanol, 1-butanol and the like. Inorder to enhance the rate of the reaction, it is advantageous to heatthe reaction mixture, in particular up to the reflux temperature.Alternatively, when P represents, for example, benzyl, the deprotectionreaction can be performed by catalytic hydrogenation in the presence ofhydrogen and an appropriate catalyst in a reaction-inert solvent. Asuitable catalyst in the above reaction is, for example,platinum-on-charcoal, palladium-on-charcoal, and the like. Anappropriate reaction-inert solvent for said reaction is, for example, analcohol, e.g. methanol, ethanol, 2-propanol and the like, an ester, e.g.ethylacetate and the like, an acid, e.g. acetic acid and the like.

The catalytic hydrogenation reaction described above can also be used toprepare a compound of formula (I-a) by deprotecting and reducing anintermediate of formula (IV) wherein Q₁ comprises an unsaturated bond,said Q₁ being represented by Q_(1a)(CH═CH), and said intermediate beingrepresented by formula (IV-a).

Compounds of formula (I) wherein, in the definition of Q, both R⁶substituents are hydrogen or R² and R⁴ are both hydrogen, said Q beingrepresented by H₂N-Q₂, and said compounds being represented by formula(I-a-1), can also be prepared by deprotecting an intermediate of formula(V).

Said deprotection reaction can be performed in the presence of asuitable base such as, for example hydrazine, or in the presence of asuitable acid, such as hydrochloric acid and the like, in a suitablesolvent, such as an alcohol, acetic acid and the like.

Compounds of formula (I-a-1) can also be prepared by deprotecting anintermediate of formula (VI) according to the procedure described forthe preparation of compounds of formula (I-a).

Compounds of formula (I-a) or (I-a-1), wherein Q₁ or Q₂ comprise ahydroxy substituent, said Q₁ or Q₂ being represented by Q_(1′)(OH) orQ_(2′)(OH), and said compounds being represented by formula (I-a-2) or(I-a-1-1), can be prepared by deprotecting an intermediate of formula(VII) or (VIII) as described hereinabove for the preparation ofcompounds of formula (I-a).

Compounds of formula (I) wherein, in the definition of Q, both R⁶substituents are hydrogen or R² and R⁴ are both hydrogen, and the carbonadjacent to the nitrogen carrying the R⁶, or R² and R⁴ substituentscontains at least one hydrogen, said Q being represented by H₂N-Q₃H, andsaid compounds being represented by formula (I-a-1-2) can also beobtained by reductive amination of intermediates of formula (IX) in thepresence of a suitable amination reagent, such as, for example, ammonia,hydroxylamine, or benzylamine, and in the presence of a suitablereducing agent, e.g. hydrogen, and an appropriate catalyst. Anappropriate catalyst in the above reaction is, for example,platinum-on-charcoal, palladium-on-charcoal, rhodium-on-Al₂O₃, and thelike, optionally in the presence of a catalyst poison, such as athiophene solution. A suitable reaction-inert solvent for the abovereaction is, for example, an alcohol, e.g. methanol, ethanol, 2-propanoland the like.

Compounds of formula (I), wherein Q comprises a —CH₂NH₂ moiety, said Qbeing represented by H₂N—CH₂-Q₄, and said compounds being represented byformula (I-a-1-3) can be prepared by reducing an intermediate of formula(X).

Said reduction can be performed with a suitable reducing agent, such aslithium aluminium hydride or hydrogen, optionally in the presence of asuitable catalyst, such as Raney Nickel. A suitable solvent for theabove reaction is, for example, tetrahydrofuran, or a solution ofammonia in an alcohol. Suitable alcohols are methanol, ethanol,2-propanol and the like. Said reduction reaction performed in a solutionof ammonia in an alcohol can also be used to prepare compounds offormula (I-a-1-3), wherein R¹ is substituted with C₁₋₆alkyloxyC₁₋₆alkyl,said R¹ being represented by R^(1′)—C₁₋₆alkyloxyC₁₋₆alkyl, and saidcompounds being represented by formula (I-a-1-3-1) starting from anintermediate of formula (X-a).

Compounds of formula (I), wherein Q comprises a —CH₂—CHOH—CH₂—NH₂moiety, said Q being represented by H₂N—CH₂—CHOH—CH₂-Q_(4′), and saidcompounds being represented by formula (I-a-1-3-2), can be prepared byreacting an intermediate of formula (XI) with ammonia in the presence ofa suitable reaction-inert solvent, such as an alcohol, e.g. methanol.

Compounds of formula (I), wherein, in the definition of Q, R² or one R⁶substituent is formyl, said Q being represented by H—C(═O)-Q¹, and saidcompounds being represented by formula (I-b), can be prepared byreacting an intermediate of formula (XII) with formic acid, formamideand ammonia.

Compounds of formula (I), wherein, in the definition of Q, R² is otherthan hydrogen, said R² being represented by R^(2a), R⁴ is hydrogen, andthe carbon atom adjacent to the nitrogen atom carrying the R² and R⁴substituents, carries also at least one hydrogen atom, said Q beingrepresented by R^(2a)—NH—HQ₅, and said compounds being represented byformula (I-c), can be prepared by reductive amination of an intermediateof formula (XIII) with an intermediate of formula (XIV) in the presenceof a suitable reducing agent, such as hydrogen, and a suitable catalyst,such as palladium-on-charcoal, platinum-on-charcoal, and the like. Asuitable reaction-inert solvent for the above reaction is, for example,an alcohol, e.g. methanol, ethanol, 2-propanol and the like.

Compounds of formula (I-c), wherein R^(2a) represents C₁₋₁₀alkylsubstituted with N(R⁶)₂ and with hydroxy, and the carbon atom carryingthe hydroxy, carries also two hydrogen atoms, said R^(2a) beingrepresented by [(C₁₋₉alkyl)CH₂OH]—N(R⁶)₂, and said compounds beingrepresented by formula (I-c-1), can be prepared by reducing anintermediate of formula (XV) in the presence of a suitable reducingagent, such as lithium aluminium hydride, in a suitable reaction-inertsolvent, such as tetrahydrofuran.

Compounds of formula (I) wherein, in the definition of Q, R² or one R⁶substituent is hydrogen, said Q being represented by H-Q₁, and whereinR¹ is aryl or a monocyclic heterocycle substituted with 1 or moresubstituents selected from hydroxy, hydroxyC₁₋₆alkyl, orHO(—CH₂—CH₂—O)_(n)—, said substituents being represented by formulaA-OH, said R¹ being represented by R^(1a)-(A-OH)_(w), with w being theamount of substituents on R^(1a) ranging from 1 to 4, and said compoundsbeing represented by formula (I-d), can be prepared by deprotecting anintermediate of formula (XVI) with a suitable acid, such as hydrochloricacid and the like, optionally in the presence of a suitable solvent,such as an alcohol. Suitable alcohols are methanol, ethanol, 2-propanoland the like.

Alternatively, one protecting group may also protect more than onesubstituent of R^(1a), said protecting group being represented by P₁, asrepresented by formula (XVI-a). The two ways of protecting thesubstituents of R^(1a), i.e. with a separate, as in formula (XVI), or acombined, as in formula (XVI-a), protecting group, may also be combinedin the same intermediate, as represented by formula (XVI-b).

Compounds of formula (I), wherein Q is a radical of formula (b-2), saidcompounds being represented by formula (I-e), can be prepared byreacting an intermediate of formula (XVII) with an intermediate offormula (XVIII) in the presence of sodium cyanide and a suitablereaction-inert solvent, such as an alcohol, e.g. methanol and the like.

Compounds of formula (I), wherein in the definition of Q, X² isC₂₋₄alkyl-NR⁴, said Q being represented by Q₆N—CH₂—C₁₋₃alkyl-NR⁴, andsaid compounds being represented by formula (I-p), can be prepared byreacting an intermediate of formula (XIX) with an intermediate offormula (XX) in the presence of isopropyl titanate (IV) and a suitablereducing agent, such as NaBH₃CN, and in the presence of a suitablereaction-inert solvent, such as methylene chloride and an alcohol, e.g.ethanol.

Compounds of formula (I-p), wherein R² is C₁₋₆alkylcarbonyl, and Q is aradical of formula (b-6), wherein Y¹ is NR², said compounds beingrepresented by formula (I-p-1), can be prepared by reacting anintermediate of formula (XIX) with an intermediate of formula (XX-a)according to the procedure described for the preparation of a compoundof formula (I-p).

Compounds of formula (I), wherein G is substituted with hydroxy orHO(—CH₂CH₂O)_(n)—, said G being represented by G₁-OH, and said compoundsbeing represented by formula (I-q), may be prepared by deprotecting anintermediate of formula (XXI), wherein P represents a suitableprotecting group, for example, benzyl. Said deprotection reaction can beperformed by catalytic hydrogenation in the presence of hydrogen and anappropriate catalyst in a reaction-inert solvent. A suitable catalyst inthe above reaction is, for example, platinum-on-charcoal,palladium-on-charcoal, and the like. An appropriate reaction-inertsolvent for said reaction is, for example, an alcohol, e.g. methanol,ethanol, 2-propanol and the like, an ester, e.g. ethylacetate and thelike, an acid, e.g. acetic acid and the like.

Compounds of formula (I), wherein G is substituted with hydroxy and thecarbon atom carrying the hydroxy substituent carries also at least onehydrogen, said G being represented by H-G₂-OH, and said compounds beingrepresented by formula (I-q-1), can also be prepared by reducing anintermediate of formula (XXII).

Said reduction reaction can be performed in the presence of a suitablereducing agent, such as, for example sodium borohydride, in areaction-inert solvent, such as an alcohol or tetrahydrofuran or amixture thereof. Suitable alcohols are methanol, ethanol, 2-propanol andthe like.

Compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions, comprising thosedescribed hereinafter.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I), wherein R¹ is monocyclic heterocyclesubstituted with C₁₋₆alkyloxycarbonyl, said R¹ being represented byR^(1′)—C(═O)OC₁₋₆alkyl, and said compounds being represented by formula(I-f), can be prepared by esterification of a compound of formula (I-g)in the presence of a suitable alcohol, e.g. methanol, ethanol, propanol,butanol, pentanol, hexanol and the like, and in the presence of asuitable acid, such as hydrochloric acid and the like.

Compounds of formula (I-a) may be converted into compounds of formula(I) wherein, in the definition of Q, R² or at least one R⁶ substituentis other than hydrogen, said R² or R⁶ being represented by Z₁, said Qbeing represented by Z₁-Q₁, and said compounds being represented byformula (I-h), by reaction with a reagent of formula (XXIII), wherein W₂is a suitable leaving group, such as a halo atom, e.g. bromo, or4-methylbenzenesulphonate, in the presence of a suitable base, such as,for example disodium carbonate, dipotassium carbonate, sodium hydroxideand the like, in a reaction-inert solvent, e.g. 3-methyl-2-butanone,acetonitrile, N,N-dimethylformamide.

Compounds of formula (I-h), wherein, in the definition of Z₁, R² isCH₂—C₁₋₉alkyl substituted with N(R⁶)₂, said compounds being representedby formula (I-h-1), can also be prepared by reacting a compound offormula (I-a) wherein, in the definition of H-Q₁, R² is hydrogen, saidH-Q₁ being represented by H-Q_(1b), and said compounds being representedby formula (I-a-3), with an intermediate of formula (XXIV), in thepresence of a suitable reducing agent, such as sodium cyanoborohydride,in a suitable reaction-inert solvent, such as an alcohol.

Compounds of formula (I-h), wherein Z₁ comprises formyl,C₁₋₆alkylcarbonyl, Hetcarbonyl or C₁₋₆alkyloxycarbonyl, said Z₁ beingrepresented by Z_(1a), and said compounds being represented by formula(I-h-2), can be converted into compounds of formula (I-a), by acidichydrolysis in the presence of a suitable acid, such as hydrobromic,hydrochloric, sulfuric, acetic, or trifluoroacetic acid or a mixture ofsaid acids, or by alkaline hydrolysis in the presence of a suitablebase, such as, for example potassium hydroxide, in a suitable solventsuch as water, alcohol, a mixture of water-alcohol, methylene chloride.Suitable alcohols are methanol, ethanol, 2-propanol, 1-butanol, sec.butanol and the like. In order to enhance the rate of the reaction, itis advantageous to work at elevated temperatures.

Compounds of formula (I-b) can be prepared by reacting a compound offormula (I-a) with formic acid.

Compounds of formula (I) wherein R¹ is monocyclic heterocycle or arylsubstituted with hydroxy, said R¹ being represented by HO—R^(1′), andsaid compounds being represented by formula (I-i), can be prepared bydeprotecting a compound of formula (I-j), wherein R¹ is monocyclicheterocycle or aryl substituted with C₁₋₆alkyloxy or arylC₁₋₆alkyloxy,said C₁₋₆alkyl or arylC₁₋₆alkyl being represented by Z₂, and said R¹being represented by Z₂-O—R^(1′). Said deprotection can be performed ina reaction-inert solvent, such as, for example methylene chloride, inthe presence of a suitable deprotecting agent, e.g. tribromoborane.

Compounds of formula (I) wherein R¹ is monocyclic heterocyclesubstituted with halo(—CH₂—CH₂—O)_(n), said compounds being representedby formula (I-k), can be converted into compounds of formula (I-1-1) or(I-1-2) by reaction with an appropriate amine of formula (XXV) or (XXVI)in a suitable reaction-inert solvent, e.g. tetrahydrofuran.

Compounds of formula (I) wherein R¹ is monocyclic heterocycle or arylsubstituted with halo, said compounds being represented by formula (I-m)can be converted into compounds of formula (I) by reaction with1-butanethiol in the presence of palladium-on-charcoal and CaO in asuitable reaction-inert solvent, such as tetrahydrofuran.

Compounds of formula (I) wherein a hydrogen atom in the radicals offormula (a-1), (a-2), (a-3), (a-4) or (a-5) is replaced by nitro, saidcompounds being represented by formula (I-n) may be reduced to acompound of formula (I-o) in the presence of a suitable reducing agent,such as hydrogen, optionally in the presence of a suitable catalyst,such as platinum-on-charcoal, and optionally in the presence of asuitable catalyst poison, e.g. a thiophene solution. The reaction may beperformed in a suitable reaction-inert solvent, such as an alcohol.

In the following paragraphs, there are described several methods ofpreparing the intermediates in the foregoing preparations. A number ofintermediates and starting materials are commercially available or areknown compounds which may be prepared according to conventional reactionprocedures generally known in the art or analogous to the proceduresdescribed in EP-A-0005318, EP-A-0099139, EP-A-0151824, EP-A-0151826,EP-A-0232937, EP-A-0295742, EP-A-0297661, EP-A-0539420, EP-A-0539421,U.S. Pat. No. 4,634,704, U.S. Pat. No. 4,695,569.

In the foregoing and the following preparations, the reaction mixture isworked up following art-known methods and the reaction product isisolated and, if necessary, further purified.

Intermediates of formula (III) can be prepared by reacting anintermediate of formula (XXVII) with a suitable leaving group, i.e. W₁,introducing agent, e.g. 1-halo-2,5-pyrrolidinedione in the presence ofdibenzoyl peroxide, in a reaction-inert solvent, e.g.tetrachloromethane.

Intermediates of formula (XXVII), wherein R¹ is monocyclic heterocycleor aryl substituted with chloro, said R¹ being represented by Cl—R^(1′)and said intermediates being represented by formula (XXVII-a) can beprepared by reacting an intermediate of formula (XXVIII), wherein(O═)R^(1b)H is defined as a carbonyl derivative of R^(1′) wherein onecarbon or nitrogen, adjacent to the carbonyl, carries at least onehydrogen, with phosphorus oxychloride. Intermediates of formula (XXVIII)may also react as their enol tautomeric forms.

Intermediates of formula (III) wherein W₁ is chloro, which is attachedto a carbon atom carrying at least one hydrogen, said G beingrepresented by G₃H, and said intermediates being represented by formula(III-a) can also be prepared by reacting an intermediate of formula(XXIX) with thionylchloride in a reaction-inert solvent, e.g.methylenechloride.

Intermediates of formula (XXIX) can be prepared by reducing anintermediate of formula (XXX) in a reaction-inert solvent, e.g. analcohol, in the presence of a suitable reducing agent, e.g. sodiumborohydride.

Alternatively, intermediates of formula (XXIX) can also be prepared bydeprotecting an intermediate of formula (XXXI), wherein P is a suitableprotecting group, e.g. C₁₋₄alkylcarbonyl, in a reaction-inert solvent,such as an alcohol, in the presence of a suitable base, e.g. sodiumhydroxide.

Intermediates of formula (XXX), wherein G₃(═O) is CH(═O), saidintermediates being represented by formula (XXX-a), can be prepared byreacting an intermediate of formula (XXXII), wherein W₃ is a suitableleaving group, such as a halo atom, e.g. bromo, withN,N-dimethylformamide in the presence of butyllithium in areaction-inert solvent, e.g. tetrahydrofuran, diethylether or a mixturethereof.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (XXXIII-a) or (XXXIII-b), wherein P represents asuitable protecting group, such as, for example, C₁₋₄alkyloxycarbonyl,with an intermediate of formula (III) according to the reactiondescribed for the general preparation of compounds of formula (I).

Intermediates of formula (IV) can also be prepared by reacting anintermediate of formula (XXXIII-a) with an intermediate of formula(XXXIV) that has reacted with methanesulfonyl chloride, in the presenceof a suitable base, such as sodium hydride, and in the presence of asuitable reaction-inert solvent, e.g. N,N-dimethylformamide.

Intermediates of formula (IV) can also be prepared by a cyclizationreaction of an intermediate of formula (XXXV) in a reaction-inertsolvent, e.g. an alcohol or N,N-dimethylformamide, in the presence ofmercury oxide and sulphur.

Intermediates of formula (IV) wherein Q₁ comprises an unsaturated bond,said Q₁ being represented by Q_(1a)(CH═CH), and said intermediates byformula (IV-a), can be prepared by reacting an intermediate of formula(XXXVI) with an intermediate of formula (III) in the presence of asuitable base, such as dipotassium carbonate.

Intermediates of formula (IV) wherein, in the definition of Q₁, the X¹or X² moieties in the radicals of formula (b-1) to (b-8) represent NH,said Q₁ being represented by Q_(1c)-NH, and said intermediates byformula (IV-b), may also be prepared by reacting an intermediate offormula (XXXVII) with an intermediate of formula (XXXVIII).

Intermediates of formula (IV) wherein R¹ is monocyclic heterocyclesubstituted with amino or mono- or di(C₁₋₆alkyl)amino, said R¹ beingrepresented by R^(5a)R^(5b)N—R^(1′), wherein R^(5a) and R^(5b) aredefined as described above, and said intermediates being represented byformula (IV-c), can be prepared by reacting an intermediate of formula(XXXIX) with an appropriate amine, represented by formula (XL), in thepresence of an appropriate catalyst, e.g. palladium, and(R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphtyl, in a suitablereaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV) wherein R¹ is monocyclic heterocyclesubstituted with C(═O)—NR^(5a)R^(5b), wherein R^(5a) and R^(5b) aredefined as described above, said R¹ being represented byR^(5a)R^(5b)N—C(═O)—R^(1′), and said intermediates being represented byformula (IV-d), can be prepared by reacting an intermediate of formula(XXXIX) with an appropriate amine, represented by formula (XL), under anatmosphere of carbon monoxide, in the presence of a suitable catalyst,e.g. palladium (II) acetate, and 1,3-bis(diphenylphosphino)propane, in asuitable reaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV) wherein P-Q₁ comprises C₁₋₁₀alkyl orC₃₋₇cycloalkyl substituted with NR⁶—P, said C₁₋₁₀alkyl or C₃₋₇cycloalkylbeing represented by Z₃, said P-Q₁ being represented by P—NR⁶-Z₃-Q_(1b),and said intermediates being represented by formula (IV-e), can beprepared by reacting a compound of formula (I-a-3) with an intermediateof formula (XLI), wherein W₄ represents a suitable leaving group, suchas p-toluenesulphonate. Said reaction can be performed in areaction-inert solvent, e.g. acetonitrile, in the presence of a suitablebase, e.g. dipotassium carbonate.

Intermediates of formula (IV-e), wherein R⁶ is hydroxyC₁₋₆alkyl, saidintermediates being represented by formula (IV-e-1), can be prepared byreacting an intermediate of formula (XLII) with an intermediate offormula (XLIII) in the presence of a suitable base, e.g. dipotassiumcarbonate, and a suitable solvent, e.g. acetonitrile.

Intermediates of formula (XXXIII-a) or (XXXIII-b) can be prepared byprotecting an intermediate of formula (XLIV) with a suitable protectinggroup, such as, for example, C₁₋₄alkyloxycarbonyl, in a reaction-inertsolvent, such as methylene chloride or an alcohol, e.g. methanol,ethanol, 2-propanol and the like, in the presence of a suitable reagent,e.g. di C₁₋₄alkyl dicarbonate and optionally in the presence of asuitable base, e.g. sodium acetate.

Alternatively, intermediates of formula (XXXIII-a) or (XXXIII-b) can beconverted into an intermediate of formula (XLIV) by reaction with asuitable acid, such as hydrochloric acid or hydrobromic acid and thelike or mixtures thereof, in the presence of a suitable solvent, e.g.water.

Intermediates of formula (XXXIII-a) or (XXXIII-b), wherein in thedefinition of Q₁, the X¹ or X² moieties in the radicals of formula (b-1)to (b-8) represent NH, said Q₁ being represented by Q_(1c)-NH, and saidintermediates by formula (XXXIII-a-1) or (XXXIII-b-1), can be preparedby reacting an intermediate of formula (XLV-a) or (XLV-b), wherein W₅represents a suitable leaving group, such as for example a halo atom,e.g. chloro, with an intermediate of formula (XLVI).

Intermediates of formula (XLV-a) or (XLV-b) can be prepared by reactingan intermediate of formula (XLVII-a) or (XLVII-b) with H₂P(═O)(W₅)₃ inthe presence of a suitable acid, e.g. hydrochloric acid.

Intermediates of formula (XLVII-a) or (XLVII-b) can be prepared byreacting an intermediate of formula (XLVII-a) or (XLVIII-b) with anintermediate of formula (IL).

Intermediates of formula (XXXIII-a) can also be prepared by reacting anintermediate of formula (XLVIII-a) with P-Q₁-C(═NH)—O—CH₂—CH₃ in areaction-inert solvent, such as an alcohol.

Intermediates of formula (XXXV) can be prepared by reacting anintermediate of formula (L) with an intermediate of formula P-Q₁=C═S,which is synthesized according to the procedures described in EP0005318, in a reaction-inert solvent, such as an alcohol, e.g. ethanol.To increase the reaction rate, the reaction may be performed at elevatedtemperatures.

Intermediates of formula (L) can be obtained by reducing an intermediateof formula (LI) in a reaction-inert solvent, e.g. an alcohol, in thepresence of a suitable reducing agent, e.g. hydrogen, and an appropriatecatalyst, e.g. Raney Nickel.

Intermediates of formula (LI) can be prepared by reacting anintermediate of formula (LII) with an intermediate of formula (LIII), inwhich W₆ represents a suitable leaving group, such as a halo atom, e.g.chloro. This reaction may be performed in a reaction-inert solvent, e.g.acetonitrile, in the presence of a suitable base, e.g. dipotassiumcarbonate.

Intermediates of formula (LII) can be prepared by reacting anintermediate of formula (LIV) with a suitable acid, such as hydrochloricacid, in the presence of a suitable solvent, e.g. an alcohol, e.g.ethanol.

Intermediates of formula (LIV) can be prepared by reacting anintermediate of formula (III) with NaN[C(═O)H]₂.

Intermediates of formula (LI) can also be prepared by reacting anintermediate of formula (LIII) with an intermediate of formula (LV) (J.Org. Chem., 25, p 1138, 1960) in a reaction-inert solvent, e.g.N,N-dimethylformamide, in the presence of an appropriate base, e.g.sodium hydride.

Intermediates of formula (XXXVI) can be prepared by dehydrating anintermediate of formula (LVI) with a suitable acid, such as sulfuricacid.

Intermediates of formula (LVI) wherein, in the definition of Q_(1a), theX¹ or X² moieties are CH₂, said Q_(1a) being represented by Q_(1a′), andsaid intermediates being represented by formula (LVI-a), can be preparedby reacting a carbonyl moiety of formula (LVII) with an intermediate offormula (LVIII) in the presence of N,N-diisopropylamine and butyllithium, in a suitable reaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV), wherein G is C₁₋₁₀alkanediyl substitutedwith C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, HO(—CH₂CH₂O)_(n)—,C₁₋₆alkyloxy(—CH₂CH₂O)_(n)—, or arylC₁₋₆alkyloxy(—CH₂CH₂O)_(n)—, saidgroup of substituents being represented by O-Z₄, said G beingrepresented by Z₄-O-G₁, and said intermediates being represented byformula (IV-f), can be prepared by reacting an intermediate of formula(XXXIII-a), with an intermediate of formula (LIX), optionally in thepresence of a suitable acid, such as p-toluenesulfonic acid and thelike, and optionally in the presence of a suitable solvent, such asN,N-dimethylacetamide. To increase the reaction rate, the reaction maybe carried out at elevated temperatures.

Intermediates of formula (LIX) can be prepared by reacting anintermediate of formula (LX) with a reagent of formula (LXI) or (LXII)in a reaction-inert solvent, such as an alcohol, or toluene, in thepresence of an acid, e.g. 4-methylbenzenesulphonic acid.

Intermediates of formula (LX) can be prepared by oxidizing anintermediate of formula (LXIII) with a suitable oxidizing agent, e.g.MnO₂, in a reaction-inert solvent, such as methylene chloride.

Intermediates of formula (IV-f) can also be prepared by reacting anintermediate of formula (IV) wherein G is C₁₋₁₀alkanediyl substitutedwith hydroxy, said G being represented by G₁-OH, and said intermediatesbeing represented by formula (IV-g), with an intermediate of formula(LXIV), wherein W₇ is a suitable leaving group, such as a halo atom,e.g. iodo, in the presence of a suitable base, e.g. sodium hydride, in areaction-inert solvent, e.g. tetrahydrofuran.

Intermediates of formula (IV-g), wherein the carbon atom of G₁ carryingthe hydroxy, also carries a hydrogen atom, said G₁-OH being representedby H-G₂-OH, and said intermediates being represented by formula(IV-g-1), can be prepared by reducing an intermediate of formula (LXV)in the presence of a suitable reducing agent, e.g. sodium borohydride,in a reaction-inert solvent, such as an alcohol, tetrahydrofuran or amixture thereof. Intermediates of formula (LXV) can also first bedeprotected, e.g. in the presence of a suitable acid, such ashydrochloric acid and the like, resulting in intermediates of formula(LXVI), followed by a reduction, resulting in a compound of formula(I-q-1) wherein Q represents H-Q₁, said compounds being represented byformula (I-q-1-1).

Intermediates of formula (IV), wherein G is ethyl substituted withhydroxy, said intermediates being represented by formula (IV-g-2) canalso be prepared by reacting an intermediate of formula (XXXIII-a) withan intermediate of formula (LXVII) in the presence of a suitable base,such as sodium hydride, in a reaction-inert solvent, such asN,N-dimethylformamide.

A subgroup of intermediates of formula (IV-g-2), represented by formula(IV-g-2-1), can also be prepared by reacting an intermediate of formula(LXVIII) with an intermediate of formula (LXIX) in the presence of1,3-dicyclohexylcarbodiimide, in a reaction-inert solvent, e.g. toluene.

Intermediates of formula (LXV) can be prepared by reacting anintermediate of formula (XXXIII-a) with an intermediate of formula(LXX), wherein W₈ is a suitable leaving group, such as a halo atom, e.g.bromo, in the presence of a suitable base, e.g. sodium hydride, in areaction-inert solvent, e.g. N,N-dimethylformamide.

Intermediates of formula (V) can be prepared by reacting an intermediateof formula (LXXI) with 1H-isoindole-1,3 (2H)-dione in the presence oftriphenylphosphine and diethyl azodicarboxylate.

Intermediates of formula (V) may also be prepared by reacting anintermediate of formula (LXXII) with 1H-isoindole-1,3 (2H)-dione in thepresence of a suitable base, such as sodium hydride, and a suitablesolvent, such as N,N-dimethylformamide.

Intermediates of formula (LXXII) can be prepared by reacting anintermediate of formula (LXXI) with an intermediate of formula (LXXIII),wherein W₉ represents a suitable leaving group, such as a halo atom,e.g. chloro, in the presence of a suitable base, such asN,N-diethyl-ethanamine, and a suitable solvent, such as methylenechloride.

Intermediates of formula (V), wherein in the definition of Q₂, R² isC₁₋₁₀alkyl, said Q₂ being represented by C₁₋₁₀alkyl-Q_(1b), and saidintermediates by formula (V-a), can be prepared by reacting a compoundof formula (I-a-3) with an intermediate of formula (LXXIV), wherein W₁₀is a suitable leaving group, such as a halo atom, e.g. chloro, in thepresence of a suitable base, such as dipotassium carbonate, and asuitable solvent, such as acetonitrile.

Intermediates of formula (LXXI) wherein, in the definition of Q₂, thecarbon atom carrying the hydroxy, also carries two hydrogen atoms, saidHO-Q₂ being represented by HO—CH₂-Q_(2′), and said intermediates beingrepresented by formula (LXXI-a), can be prepared by reducing anintermediate of formula (LXXV) in the presence of a suitable reducingagent, such as lithium aluminium hydride, in a suitable reaction-inertsolvent, e.g. tetrahydrofuran.

Intermediates of formula (LXXI), wherein, in the definition of Q₂, thecarbon atom carrying the hydroxy, carries also at least one hydrogen,said HO-Q₂ being represented by HO-Q₃H, and said intermediates beingrepresented by formula (LXXI-b), can be prepared by reducing anintermediate of formula (IX) with a suitable reducing agent, e.g. sodiumborohydride, in a reaction-inert solvent, e.g. an alcohol.

Intermediates of formula (VI) wherein, in the definition of Q₂, R² isC₁₋₁₀alkyl substituted with N(P)₂ and the carbon atom adjacent to thenitrogen atom carrying the R² substituent carries also at least onehydrogen atom, said Q₂ being represented by (P)₂N—C₁₋₁₀alkyl-NH-Q_(2a)H,and said intermediates being represented by formula (VI-a), can beprepared by reductive amination of an intermediate of formula (LXXVI)with an intermediate of formula (LXXVII) in the presence of a suitablereductive agent, such as hydrogen, and a suitable catalyst, such aspalladium-on-charcoal, platinum-on-charcoal, and the like, andoptionally in the presence of a suitable catalyst poison, such as athiophene solution. A suitable solvent in this reaction is areaction-inert solvent, such as an alcohol.

Intermediates of formula (LXXVI) can be prepared by deprotecting anintermediate of formula (LXXVIII) in the presence of a suitable acid,such as hydrochloric acid and the like, in a suitable solvent, e.g.water.

Intermediates of formula (IX) may be prepared by deprotecting anintermediate of formula (LXXIX) in the presence of a suitable acid, e.g.hydrochloric acid and the like.

Intermediates of formula (LXXIX) can be prepared by reacting anintermediate of formula (LXXX) with an intermediate of formula (III) inthe presence of a suitable base, e.g. dipotassium carbonate, in asuitable reaction-inert solvent, e.g. acetonitrile.

Intermediates of formula (LXXX) wherein, in the definition of Q₃, the X¹or X² moiety of the radicals of formula (b-1) to (b-8) represent NH,said Q₃ being represented by Q_(3′)—NH, and said intermediates beingrepresented by formula (LXXX-a), may be prepared by cyclizing anintermediate of formula (LXXXI) in the presence of mercury oxide andsulphur, in a suitable reaction-inert solvent, e.g. an alcohol.

Intermediates of formula (LXXXI) can be prepared by reducing anintermediate of formula (LXXXII) in the presence of a suitable reducingagent, such as hydrogen, in the presence of a suitable catalyst, such aspalladium-on-charcoal, platinum-on-charcoal and the like, in a suitablesolvent, e.g. a mixture of ammonia in alcohol. Suitable alcohols aremethanol, ethanol, 2-propanol and the like.

Intermediates of formula (LXXXII) can be prepared by reacting anintermediate of formula (LXXXIII) with an intermediate of formula(LXXXIV) in a suitable reaction-inert solvent, e.g. ethanol.

Intermediates of formula (IX), wherein, in the definition of Q₃, R²comprises C₁₋₁₀alkyl, said Q₃ being represented by C₁₋₁₀alkyl-Q_(1b),and said intermediates being represented by formula (IX-a), can beprepared by reacting a compound of formula (I-a-3) with a reagent offormula (LXXXV), wherein (O═)C₁₋₁₀alkyl represents a carbonyl derivativeof C₁₋₁₀alkyl and wherein W₁₁ is a suitable leaving group, such as ahalo atom, e.g. bromo, in a reaction-inert solvent, e.g. acetonitrile,in the presence of a suitable base, e.g. dipotassium carbonate.

Intermediates of formula (X) wherein Q₄ comprises C₁₋₉alkyl, said Q₄being represented by C₁₋₉alkyl-Q_(1b), and said intermediates beingrepresented by formula (X-a), can be prepared by reacting a compound offormula (I-a-3) with a reagent of formula (LXXXVI) wherein W₁₂represents a suitable leaving group, such as a halo atom, e.g. chloro,in a reaction-inert solvent, e.g. 3-methyl-2-butanone, in the presenceof a suitable base, e.g. dipotassium carbonate, sodium bicarbonate andthe like.

Intermediates of formula (X), wherein NC-Q₄ representsNC—(C₁₋₉alkyl)(R⁴)N—C(═O)-Alk-X¹, said intermediates being representedby formula (X-b), can be prepared by reacting an intermediate of formula(LXXXVII) with an intermediate of formula (LXXXVIII) in the presence ofdi-1H-imidazol-2-yl-methanone, a suitable base, such asN,N-diethyl-ethanamine, and a suitable solvent, such as methylenechloride.

Intermediates of formula (XI), wherein Q_(4′) represents Q_(1b), saidintermediates being represented by formula (XI-a), can be prepared byreacting a compound of formula (I-a-3) with an intermediate of formula(LXXXIX), wherein W₁₃ represents a suitable leaving group, such as ahalo atom, e.g. chloro, in the presence of a suitable base, such asdisodium carbonate, and in the presence of a suitable solvent, such as3-methyl-2-butanone.

Intermediates of formula (XIX) can be prepared by reacting anintermediate of formula (XC) with a suitable acid, such as hydrochloricacid.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid, respectively chiral base. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography, in particular liquid chromatographyusing a chiral stationary phase. Said pure stereochemically isomericforms may also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereaction occurs stereospecifically. Preferably if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The compounds of formula (I) show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV).

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, particularly their anti-RSVproperties, the compounds of formula (I) or any subgroup thereof, theirprodrugs, N-oxides, addition salts, quaternary amines, metal complexesand stereochemically isomeric forms, are useful in the treatment ofindividuals experiencing a viral infection, particularly a RSVinfection, and for the prophylaxis of these infections. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses, in particular therespiratory syncytial virus.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the RSV infection.

The present invention also relates to the use of the present compoundsor any subgroup thereof in the manufacture of a medicament for thetreatment or the prevention of viral infections, particularly RSVinfection.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form ormetal complex, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, particularly, foradministration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin.

The compounds of the present invention may also be administered via oralinhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder, a solution beingpreferred. Any system developed for the delivery of solutions,suspensions or dry powders via oral inhalation or insufflation aresuitable for the administration of the present compounds.

Thus, the present invention also provides a pharmaceutical compositionadapted for administration by inhalation or insufflation through themouth comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Preferably, the compounds of the present inventionare administered via inhalation of a solution in nebulized oraerosolized doses.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections.

The following examples are intended to illustrate the present invention.

A. PREPARATION OF THE INTERMEDIATE COMPOUNDS EXAMPLE A1

a) K₂CO₃ (0.129 mol) was suspended in a solution of ethyl4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (0.0347 mol) and2-bromo-1-(4-chlorophenyl)ethanone (0.0647 mol) in acetonitrile (150ml). The mixture was stirred and refluxed for 8 hours, then cooled,poured out into H₂O and extracted with CH₂Cl₂. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97.5/2.5/0.1). The pure fractions were collected andthe solvent was evaporated. Part of this fraction (3 g) was taken up in2-propanone and diethyl ether. The precipitate was filtered off anddried, yielding 2 g of ethyl4-[[1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 1).

b) A mixture of intermediate (1) (0.015 mol) in HCl 12N (100 ml) wasstirred and refluxed for 12 hours, then the solvent was evaporated.Ethylacetate was added. The mixture was basified with a saturated NaHCO₃solution. The precipitate was filtered off, washed with H₂O and withethylacetate and dried. The residue (5.5 g) was crystallized fromethylacetate. The precipitate was filtered off and dried, yielding 4.8 gof1-(4-chlorophenyl)-2-[2-(4-piperidinylamino)-1H-benzimidazol-1-yl]ethanonedihydrate (80%) (interm. 2).

EXAMPLE A2

a) NaBH4 (0.034 mol) was added portionwise at 5° C. to a mixture of(±)-1,1-dimethylethyl4-[[1-(2-oxo-2-phenylethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(0.034 mol) in tetrahydrofuran (250 ml) and methanol (250 ml). Themixture was stirred at 5° C. and then hydrolyzed cold with H₂O. Thesolvent was evaporated and the residue was taken up in H₂O. Theprecipitate was filtered off, washed with diisopropylether and dried,yielding 11.3 g of (±)-1,1-dimethylethyl4-[[1-(2-hydroxy-2-phenylethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(76%) (interm. 3).

b) A mixture of intermediate (3) (0.0183 mol) in tetrahydrofuran (50 ml)was cooled to 0° C. under N₂ flow. NaH 80% (0.0366 mol) was addedportionwise. The mixture was brought to room temperature, then stirredat room temperature for 30 minutes and cooled again to 0° C. A solutionof CH₃I (0.0183 mol) in tetrahydrofuran (50 ml) was added dropwise. Themixture was stirred at room temperature for 2 hours, then cooled,hydrolyzed and extracted with ethylacetate. The organic layer wasseparated, washed with H₂O, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98.5/1.5/0.1). The desiredfractions were collected and the solvent was evaporated, yielding 5 g of(±)-1,1-dimethylethyl4-[[1-(2-methoxy-2-phenylethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 4).

EXAMPLE A3

a) NaOCH₃ (0.2 mol) was added to a mixture ofN-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide (0.1 mol) inmethanol (389 ml), the mixture was cooled on an ice bath and stirred for2 hours. Bis(1,1-dimethylethyl)dicarbonoate (0.1 mol) was added to acooled mixture on an ice bath and then stirred for 18 hours at roomtemperature. The solvent was evaporated and the residue suspended inwater/diisopropyl ether. The residue was filtered off, washed withwater/diisopropyl ether and dried. The residue was boiled up in CH₃OH,yielding 17.46 g of 1,1-dimethylethyl4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (55.2%) (interm.5).

b) A mixture of 3-(benzyloxy)-6-methyl-2-pyridinemethanol (0.0314 mol)and MnO₂ (29.52 g) in CH₂Cl₂ (100 ml) was stirred at room temperatureovernight and then purified over silica gel on a glass filter (eluent:CH₂Cl₂ 100%). The pure fractions were collected and the solvent wasevaporated, yielding 6.71 g of6-methyl-3-(phenylmethoxy)-2-pyridinecarboxaldehyde (94%) (interm. 6).

c) A mixture of intermediate (6) (0.0385 mol) and triethylorthoformiatein the presence of 4-methylbenzenesulfonic acid (0.5 g) in toluene (200ml) was stirred and refluxed for 6 hours. The solvent was evaporated.The residue was taken up in H₂O, Na₂CO₃ and CH₂Cl₂. The organic layerwas separated, dried, filtered and the solvent was evaporated, yielding9.6 g of 2-(diethoxymethyl)-6-methyl-3-(phenylmethoxy)pyridine (83%)(intern. 7).

d) Intermediate (7) (0.03185 mol) and intermediate (5) (0.03185 mol)were heated to 150° C. and purified over silica gel on a glass filter(eluent: CH₂Cl₂/(CH₃OH/NH₃) 98/2). The pure fractions were collected andthe solvent was evaporated, yielding 10.25 g of (±)-1,1-dimethylethyl4-[[1-[ethoxy[6-methyl-3-(phenylmethoxy)-2-pyridinyl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(56%) (interm. 8).

e) A mixture of 2-(diethoxymethyl)-6-bromo-pyridine (0.03 mol),intermediate 5 (0.03 mol) and 4-methylbenzenesulfonic acid (2 g) intoluene (700 ml) was stirred and refluxed for 20 hours using a waterseparator. 4-Methylbenzenesulfonic acid was added and the mixture wasstirred and refluxed for 48 hours 4-Methylbenzenesulfonic acid was addedagain and the mixture was stirred and refluxed for another 48 hours.4-Methylbenzenesulfonic acid was added again. The mixture was stirredand refluxed for 24 hours, then cooled and washed with a diluted NaOHsolution. The organic layer was separated, dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/C₂H₅OH 95/5). The purefractions were collected and the solvent was evaporated. The residue wassuspended in petroleum ether. The precipitate was filtered off anddried, yielding 1.4 g of (±)-1,1-dimethylethyl4-[[1-[(6-bromo-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(9%) (interm. 33).

EXAMPLE A4

a) A mixture of 2,3-pyridinediamine (0.05 mol) and ethyl4-(2-ethoxy-2-iminoethyl)-1-piperidinecarboxylate monohydrochloride(0.05 mol) in methanol (150 ml) was stirred and refluxed for 3 days. Thesolvent was evaporated and the residue was taken up in CH₂Cl₂. Theorganic solution was washed with K₂CO₃ 10%, dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.1).The pure fractions were collected and the solvent was evaporated,yielding 7.6 g of ethyl4-[(1H-imidazo[4,5-b]pyridin-2-yl)methyl]-1-piperidinecarboxylate (52%)(interm. 9).

b) NaH (0.028 mol) was added portionwise at 0° C. to a mixture ofintermediate (9) (0.023 mol) in N,N-dimethylformamide (75 ml).2-Bromo-1-phenylethanone (0.028 mol) was added. The mixture was stirredat room temperature for 1 hour. H₂O was added and the mixture wasextracted with ethylacetate. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97.5/2.5/0.1). The pure fractions were collected and the solvent wasevaporated, yielding 4.7 g of ethyl4-[[1-(2-oxo-2-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinecarboxylate(50.5%) (interm. 10).

c) NaBH₄ (0.0137 mol) was added portionwise at 5° C. under N₂ flow to amixture of intermediate (10) (0.0137 mol) in methanol (100 ml). Themixture was hydrolyzed with H₂O and extracted with ethylacetate. Theorganic layer was separated, dried, filtered and the solvent wasevaporated, yielding 5.6 g of (±)-ethyl4-[[1-(2-hydroxy-2-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinecarboxylate(interm. 11).

EXAMPLE A5

A mixture of(±)-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine(0.00205 mol), 1-chloro-2-propanone (0.00308 mol) and K₂CO₃ (0.0041 mol)in acetonitrile (8 ml) was stirred and refluxed for 8 hours. H₂O wasadded and the mixture was extracted with ethylacetate. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1). The pure fractions were collected and thesolvent was evaporated, yielding: 0.67 g of(±)-1-[4-[[1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-propanone(77%) (interm. 12).

EXAMPLE A6

4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at10° C. to a mixture of 1,1-dimethylethyl[1-(hydroxymethyl)-2-methylpropyl]carbamoate (0.202 mol) in pyridine (65ml). The mixture was stirred at 10° C. for 2 hours. H₂O (75 ml) wasadded at 10° C. The precipitate was filtered off, washed with H₂O andtaken up in CH₂Cl₂. The organic solution was washed with H₂O, dried,filtered and the solvent was evaporated, yielding 49 g of(±)-1,1-dimethylethyl[1-[[[(4-methylphenyl)-sulfonyl]oxy]methyl]-2-methylpropyl]carbamate(68%) (interm. 13).

EXAMPLE A7

a) A mixture of (±)-1,1-dimethylethyl4-[[1-[(6-bromo-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(0.00189 mol) (interm. 33), Pd (0.026 g),(R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphtyl (0.046 g) andNH(CH₃)₂ gas (10 g) in tetrahydrofuran (200 ml) was stirred in anautoclave at 100° C. for 16 hours under pressure of CO (30 atm). Themixture was filtered and the filtrate was evaporated. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/(CH₃OH/NH₃)99/1). The pure fractions were collected and the solvents wasevaporated, yielding 0.8 g of (±)-1,1-dimethylethyl4-[[1-[[6-(dimethylamino)-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(86%) (interm. 14).

b) A mixture of intermediate 33 (0.0032 mol), Pd(OAc)₂ (0.030 g) and1,3-propanediylbis[diphenylphosphine] (0.110 g) in tetrahydrofuran (100ml) under ammonia (liq., 10 atm) and CO (gas, 30 atm) was stirred for 16hours at 100° C. The solvent was evaporated. The residue was purifiedover silica gel on a glass filter (eluent: CH₂Cl₂/(CH₃OH/NH₃) 98/2). Thepure fractions were collected and the solvent was evaporated, yielding0.15 g of interm. 41.

EXAMPLE A8

A mixture of α-[[(3-amino-2-pyridinyl)amino]methyl]benzenemethanol(0.043 mol) and ethyl 4-isothiocyanato-1-piperidinecarboxylate (0.047mol) in toluene (200 ml) was stirred and refluxed for 30 minutes.N,N′-methanetetrayl-biscyclohexanamine (0.065 mol) was added and themixture was stirred and refluxed overnight. The solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH₄OH 96/4/0.2). The pure fractions were collectedand the solvent was evaporated. Part of the residue (1.5 g) wascrystallized from diisopropyl ether. The precipitate was filtered offand dried, yielding 1.35 g of (±)-ethyl4-[[1-(2-hydroxy-2-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate(interm. 15).

EXAMPLE A9

Reaction under N₂ flow. NaH 60% (0.02 mol) was added to a mixture of1.1-dimethylethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate(0.02 mol) in N,N-di-methylformamide (100 ml). The mixture was stirredat 40° C. for 1 hour. 6-(Epoxyethyl)-2-picoline (0.02 mol) in a smallamount of N,N-dimethylformamide was added. The mixture was stirred at100° C. overnight. The solvent was evaporated. The residue was taken upin H₂O and CH₂Cl₂. The organic layer was separated, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5 and 90/10).The pure fractions were collected and the solvent was evaporated,yielding 3.5 g of (±)-1,1-dimethylethyl4-[[1-[2-hydroxy-2-(6-methyl-2-pyridinyl)ethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(interm. 16).

Tables 1, 2 and 3 list intermediates which were prepared analogous toone of the above examples.

TABLE 1

Int. Ex. No. No. L R^(a) Physical data 17 A1b H 2-Cl 18 A1b H 4-OCH₃ 19A1b H 3-Cl H₂O (1:1) 20 A1b H 3-F H₂O (1.2) 2 A1b H 4-Cl H₂O (1:2) 21A1b H 3-CH₃ 22 A1b H 2-CH₃ H₂O (1:1) 23 A1a —C(═O)—O—C₂H₅ 4-CH₃ 24 A1b H4-CH₃ H₂O (1:1); mp. 180° C. 25 A1b H 3-OCH₃ H₂O (1:1), HCl (1:1); mp.220° C. 26 A1b H 2-F

TABLE 2

Physical Int. Ex. data; No. No. L n a b R^(a) R^(b) R^(c) mp. 27 A3e—C(═O)—O—C(CH₃)₃ 0 N CH CH₃ —C₂H₅ H 28 A3d —C(═O)—O—C(CH₃)₃ 0 N CH CH₃

H 29 A3d —C(═O)—O—C(CH₃)₃ 0 N CH CH₃ —(CH₂)₂—O—C₂H₅ H 30 A3d—C(═O)—O—C(CH₃)₃ 0 N CH CH₃ —[(CH₂)₂—O]₂—CH₃ H 31 A3d —C(═O)—O—C(CH₃)₃ 0N CH Phenyl —(CH₂)₂—O—C₂H₅ H 32 A3d —C(═O)—O—C(CH₃)₃ 0 N CH —CH₂—O—CH₃—CH₃ H 33 A3e —C(═O)—O—C(CH₃)₃ 0 N CH Br —C₂H₅ H 34 A3d —CH₂-phenyl 0 NCH H —C₂H₅ H 35 A5 —CH₂—C(═O)—CH(CH₃)₂ 0 N CH CH₃ —C₂H₅ H 36 A5—CH₂—C(═O)—CH(CH₃)₂ 0 N CH CH₃ —(CH₂)₂—O—C₂H₅ H 37 A5—CH₂—C(═O)—CH(CH₃)₂ 0 N CH CH₃ —[(CH₂)₂—O]₂—CH₃ H 38 A5—CH₂—C(═O)—CH(CH₃)₂ 0 N CH Phenyl —(CH₂)₂—O—C₂H₅ H 40 A3d—C(═O)—O—C(CH₃)₃ 0 N CH CH₃ —C₂H₅ 3-O- benzyl 41 A7b —C(═O)—O—C(CH₃)₃ 0N CH —CO—NH₂ —C₂H₅ H 42 A7b —C(═O)—O—C(CH₃)₃ 0 N CH —CO—N(CH₃)₂ —C₂H₅ H16 A9 —C(═O)—O—C(CH₃)₃ 1 N CH CH₃ H H 44 A3d —C(═O)—O—C(CH₃)₃ 0 N CH CH₃—(CH₂)₂—OCH₃ H 4 A2b —C(═O)—O—C(CH₃)₃ 1 CH CH H CH₃ H 15 A8—C(═O)—O—C₂H₅ 1 CH N H H H 85° C. 47 A7a —C(═O)—O—C(CH₃)₃ 0 N CH—N(CH₃)₂ C₂H₅ H

TABLE 3

Int. Ex. No. No. b R^(a) R^(b) R^(c) L Physical data; mp. 48 A3d CH Br—CH₂—CH₃ H —C(═O)—O—C(CH₃)₃ 49 A5 CH CH₃ —C₂H₄—O—CH₃ Cl—CH₂—C(═O)—CH(CH₃)₂ 50 A3d CH CH₃ —C₂H₄—O—CH₃ Cl —C(═O)—O—C(CH₃)₃ 51 A5N CH₃ —C₂H₄—O—CH₃ H —CH₂—C(═O)—CH(CH₃)₂ 52 A3d N CH₃ —C₂H₄—O—CH₃ H—CH₂—C₆H₅

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B1

A mixture of intermediate (4) (0.0102 mol) in HCl 3N (80 ml) and2-propanol (10 ml) was stirred at 40° C. for 2 hours. The mixture wasbrought to room temperature and poured out on ice. CH₂Cl₂ was added. Themixture was basified with K₂CO₃ solid, stirred at room temperature for 1hour and extracted with CH₂Cl₂. The organic layer was separated, washedwith H₂O, dried, filtered and the solvent was evaporated. The residuewas crystallized from diethyl ether and CH₃OH. The precipitate wasfiltered off and dried, yielding 2.9 g of(±)-1-(2-methoxy-2-phenylethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine(81%) (compound 1).

EXAMPLE B2

A mixture of intermediate (11) (0.0139 mol) and KOH (0.1 mol) in2-propanol (200 ml) was stirred and refluxed overnight. The solvent wasevaporated and the residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 80/20/3). The pure fractions werecollected and the solvent was evaporated. The residue was converted intothe ethanedioic acid salt (1:2) with ethanedioic acid. The mixture wascrystallized from 2-propanone. The precipitate was filtered off anddried, yielding 3.9 g of(±)-α-phenyl-2-(4-piperidinylmethyl)-1H-imidazo[4,5-b]pyridine-1-ethanolethanedioate (1:2) (compound 2).

EXAMPLE B3

a) A mixture of intermediate (8) (0.00175 mol) in trifluoroacetic acid(20 ml) and CH₂Cl₂ (50 ml) was stirred at room temperature for 2 hours,poured out into ice water and alkalized with a NaOH solution. CH₂Cl₂ wasadded. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified over silica gel on a glassfilter (eluent: CH₂Cl₂/(CH₃OH/NH₃) 90/10). The pure fractions werecollected and the solvent was evaporated. The residue was converted intothe hydrochloric acid salt (1:3). The precipitate was filtered off anddried, yielding 0.48 g of(±)-1-[ethoxy[6-methyl-(3-phenylmethoxy)-2-pyridinyl]methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-aminetrihydrochloride dihydrate 2-propanolate (1:1) (compound 3).

b) A mixture of (±)-1,1-dimethylethyl4-[[1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(0.0026 mol) in 2-propanol (30 ml) and HBr/CH₃COOH (2 ml) was stirredand refluxed for 2 hours and then cooled. The solvent was evaporated.The residue was taken up in H₂O and CH₂Cl₂. The mixture was alkalizedwith a NaOH solution. The organic layer was separated, washed with H₂O,dried, filtered and the solvent evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/NH₃ 90/10). Thepure fractions were collected and the solvent was evaporated. Theresidue was suspended in petroleum ether. The precipitate was filteredoff and dried. This fraction was recrystallized from a small amount ofCH₃CN. The precipitate was filtered off and dried, yielding 0.22 g of(±)-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine(19.6%) (compound 4).

EXAMPLE B4

A mixture of(±)-1-[ethoxy(2-pyridinyl)methyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-amine(0.011 mol) in methanol (150 ml) was hydrogenated for 4 days with Pd/C10% (2 g) as a catalyst. After uptake of H₂ (1 equivalent), the catalystwas filtered off and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃) 90/10). The pure fractions were collected and thesolvent was evaporated, yielding 1.5 g of(±)-1-[ethoxy-(2-pyridinyl)methyl]-N-(4-piperidinyl)-2-benzimidazol-2-amine(39%) (compound 5).

EXAMPLE B5

NaBH₄ (0.0078 mol) was added portionwise to a mixture of intermediate(2) (0.0078 mol) in tetrahydrofuran (50 ml) and methanol (50 ml), andthe mixture was stirred at 5° C. under N₂ flow for 2 hours. The mixturewas hydrolyzed cold with H₂O (3 ml) and the solvent was evaporated. Theprecipitate was filtered off, washed with H₂O and dried.

The residue (3 g) was crystallized from diisopropyl ether. Theprecipitate was filtered off and dried, yielding 2.9 g of(±)-α-(4-chlorophenyl)-2-(4-piperidinylamino)-1H-benzimidazole-1-ethanol(100%) (compound 6).

EXAMPLE B6

A mixture of compound (4) (0.0035 mol), 1,1-dimethylethyl(2-bromomethyl)carbamoate (0.005 mol) and Na₂CO₃ (0.01 mol) in2-butanone (100 ml) was stirred and refluxed for 20 hours. H₂O wasadded. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 95/5 to 90/10). The pure fractions werecollected and the solvent was evaporated, yielding 1.3 g of(±)-1,1-dimethylethyl[2-[4-[[1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]carbamate(compound 7).

EXAMPLE B7

A mixture of compound (4) (0.00348 mol), intermediate (13) (0.00348 mol)and K₂CO₃ (0.01392 mol) in acetonitrile (20 ml) andN,N-dimethylformamide (4 ml) was stirred at 60° C. for 4 hours (1equivalent of intermediate (13) was added every hour) and then cooled.The solvent was evaporated. The residue was taken up in CH₂Cl₂. Theorganic solution was washed with H₂O, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96.5/3.5/0.1). Two pure fractionswere collected and their solvents were evaporated, yielding Ig of(±)-1,1-dimethylethyl[1-[[4-[[1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]methyl]-2-methylpropyl]carbamate(47%) (compound 8).

EXAMPLE B8

A mixture of compound (7) (0.0026 mol) in 2-propanol (30 ml) andHBr/acetic acid (2 ml) was stirred and refluxed for 90 minutes and thencooled. The solvent was evaporated. The residue was taken up in CH₂Cl₂and H₂O. The organic layer was separated, dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 90/10). Thepure fractions were collected and the solvent was evaporated. Theresidue was suspended in diisopropyl ether. The precipitate was filteredoff and dried. This fraction was purified again by column chromatographyover silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 90/10). The pure fractionswere collected and the solvent was evaporated. The residue was suspendedin diisopropyl ether. The precipitate was filtered off and dried,yielding 0.23 g of(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-amine(compound 9).

EXAMPLE B9

A mixture of compound (8) (0.00162 mol) in 2-propanol/HCl (1 ml) and2-propanol (10 ml) was stirred and refluxed for 1 hour and then cooled.The solvent was evaporated. The residue was taken up in CH₂Cl₂. Theorganic solution was washed with K₂CO₃ 10% and with H₂O, dried, filteredand the solvent was evaporated. The residue was purified by columnchromatography (eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/1). The pure fractionswere collected and the solvent was evaporated, yielding 0.23 g of(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(6-bromo-2-pyridinyl)-ethoxymethyl]-1H-benzimidazol-2-amine(27%) (compound 10).

EXAMPLE B10

A mixture of (±)-1,1-dimethylethyl[2-[4-[[1-[ethoxy[6-methyl-3-(phenylmethoxy)-2-pyridinyl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamate(0.0016 mol) and KOH (1 g) in sec-butanol (25 ml) was stirred andrefluxed for 6 hours. The solvent was evaporated. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/(CH₃OH/NH₃)95/5, 93/7 to 90/10). The pure fractions were collected and the solventwas evaporated. The residue was converted into the hydrochloric acidsalt (1:3). The precipitate was filtered off and dried, yielding 0.5 gof(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[ethoxy[6-methyl-3-(phenylmethoxy)-2-pyridinyl]-methyl]-1H-benzimidazol-2-aminetrihydrochloride dihydrate (compound 11).

EXAMPLE B11

A mixture of intermediate (12) (0.0016 mol) and benzenemethanamine(0.0048 mol) in methanol (7 ml) was hydrogenated at 40° C. under a 5 barpressure for 8 hours with Pd/C (0.07 g) as a catalyst. After uptake ofH₂ (1 equivalent), the catalyst was filtered through celite, washed withCH₃OH and CH₂Cl₂ and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.7). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from diethyl ether.The precipitate was filtered off and dried, yielding 0.4 g of(±)-N-[1-(2-aminopropyl)-4-piperidinyl]-1-[ethoxy(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine(59%) (compound 12).

EXAMPLE B12

A mixture of(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(6-methyl-2-pyridinyl)[2-(phenylmethoxy)ethoxy]methyl]-1H-benzimidazol-2-amine (0.003 mol) inmethanol (150 ml) was stirred at room temperature with Pd/C 10% (0.5 g)as a catalyst. After uptake of H₂ (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃)90/10). The pure fractions were collected and the solvent wasevaporated. The residue was suspended in petroleum ether. Theprecipitate was filtered off and dried, yielding 0.23 g of(±)-2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]-amino]-1H-benzimidazol-2-yl](6-methyl-2-pyridinyl)methoxy]ethanolmonohydrate (18%) (compound 13).

EXAMPLE B13

A mixture of(±)-1-[4-[[1-(2-ethoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone(0.0032 mol) in NH₃/CH₃OH (200 ml) was hydrogenated for 3 days at 20° C.with Rh/Al₂O₃ 5% (1 g) as a catalyst in the presence of a thiophenesolution (2 ml). After uptake of H₂ (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃)95/5). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from diisopropyl ether, filtered off anddried, yielding 0.58 g of(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)(6-methyl-2-pyridinyl)methyl]-1H-benzimidazol-2-amine(compound 14).

Tables 4 to 8 list the compounds of formula (I) which were preparedaccording to one of the above examples.

TABLE 4

Comp. Ex. Physical No. No. b c a L R^(b) R^(a) data 1 B1 NH CH CH H CH₃H mp. 146° C. 2 B2 CH₂ N CH H H H mp. 150° C.; ethanedioate (1:2) 6 B5NH CH CH H H 4-Cl 31 B2 NH N CH H H H mp. 210° C. 32 B5 NH CH CH H H2-Cl 33 B5 NH CH CH H H 4-OCH₃ 34 B5 NH CH CH H H 3-Cl 35 B5 NH CH CH HH 2-CH₃ 36 B5 NH CH CH H H 3-CH₃ mp. 145° C. 37 B5 NH CH CH H H 3-OCH₃mp. 162° C. 38 B5 NH CH CH H H 3-F mp. >230° C. 39 B5 NH CH CH H H 2-Fmp. 205° C. 40 B5 NH CH CH H H 4-CH₃ mp. 207° C. 47 B6 NH CH N * H3-CH₃ * = —(CH₂)₂—NH—C(═O)—O—C(CH₃)₃

TABLE 5

Comp. Ex. Physical No. No. L R^(a) R^(b) R^(c) data 3 B3a H CH₃ —C₂H₅ **HCl (1:3); H₂O (1:2); 2-propanolate (1:1) 4 B3b H Br —C₂H₅ H 5 B4 H H—C₂H₅ H 9 B8 —(CH₂)₂—NH₂ Br —C₂H₅ H 11 B10 —(CH₂)₂—NH₂ CH₃ —C₂H₅ ** HCl(1:3); H₂O (1:2) 13 B12 —(CH₂)₂—NH₂ CH₃ —C₂H₄—OH H H₂O (1:1) 15 B1 H CH₃—C₂H₅ H 16 B1 H CH₃ —(CH₂)₂—O—C₂H₅ H 17 B1 H CH₃ —[(CH₂)₂—O]₂—CH₃ H 18B1 H CH₃ —C₂H₅ H (A) 19 B1 H Br —C₂H₅ H (A) 20 B1 H Br —C₂H₅ H (B) 21 B1H CH₃ —C₂H₅ H (B) 22 B1 H —CH₂—O—CH₃ —CH₃ H 23 B1 H Phenyl—(CH₂)₂—O—C₂H₅ H 24 B1 H —N(CH₃)₂ —C₂H₅ H 25 B1 H —C(═O)—NH₂ —C₂H₅ H 26B1 H —C(═O)—N(CH₃)₂ —C₂H₅ H 27 B1 H CH₃ H H 28 B1 H CH₃ H H HCl (1:3);H₂O (1:1) 29 B1 H CH₃ —(CH₂)₂—O—CH₂— H phenyl 30 B1 H CH₃ —(CH₂)₂—O—CH₃H HCl (1:1) 63 B9 —(CH₂)₂—NH₂ CH₃ —C₂H₅ H 64 B9 —(CH₂)₂—NH₂ CH₃—C₂H₄—O—C₂H₅ H 65 B9 —(CH₂)₂—NH₂ H —C₂H₅ H HCl (1:4); H₂O (1:1) 66 B9—(CH₂)₂—NH₂ H —[(CH₂)₂—O]₂—CH₃ H 78 B9 —(CH₂)₂—NH₂ phenyl —C₂H₄—O—C₂H₅ HHCl (1:3); H₂O (1:1) 79 B9 —(CH₂)₂—NH₂ —N(CH₃)₂ —C₂H₅ H HCl (1:4); H₂O(1:3) 80 B9 —(CH₂)₂—NH₂ CH₃ H H HCl (1:4); H₂O (1;1) 81 B9 —(CH₂)₂—NH₂CH₃ —C₂H₄—O—CH₂— H phenyl 82 B9 —(CH₂)₂—NH₂ CH₃ —C₂H₄—O—CH₃ H ** =—O—CH₂-phenyl (A) indicates the first isolated stereoisomeric form (B)indicates the second isolated stereoisomeric form

TABLE 6

Comp. Ex. Physical No. No. R^(a) R^(b) R^(c) R^(d) data 7 B6 Br —C₂H₅ HH 8 B7 Br —C₂H₅ H —CH(CH₃)₂ 41 B6 CH₃ —C₂H₅ H H 42 B6 CH₃ —C₂H₄—O—C₂H₅ HH 43 B6 H —C₂H₅ H H 44 B6 CH₃ —[C₂H₄—O]₂—CH₃ H H 45 B6 phenyl—C₂H₄—O—C₂H₅ H H 46 B6 —N(CH₃)₂ —C₂H₅ H H 48 B6 CH₃ —C₂H₄—O—CH₂-phenyl HH 49 B6 CH₃ —C₂H₄—O—CH₃ H H 50 B6 CH₃ —C₂H₅ —O—CH₂-phenyl H 51 B7 CH₃—C₂H₅ H —CH(CH₃)₂ [(A),(S)] 52 B7 CH₃ —C₂H₅ H —CH(CH₃)₂ [(A),(R)] 53 B7Br —C₂H₅ H —CH(CH₃)₂ [(A),(S)] 54 B7 Br —C₂H₅ H —CH(CH₃)₂ [(A),(R)] 55B7 Br —C₂H₅ H —CH(CH₃)₂ [(B),(R)] 56 B7 Br —C₂H₅ H —CH(CH₃)₂ [(B),(S)]57 B7 CH₃ —C₂H₅ H —CH(CH₃)₂ [(B),(S)] 59 B7 CH₃ —C₂H₅ H —CH₃ [(A),(R)]60 B7 CH₃ —C₂H₅ H —CH₃ [(A),(S)] 61 B7 CH₃ —C₂H₅ H —CH₃ [(B),(S)] 62 B7CH₃ —C₂H₅ H —CH₃ [(B),(R)] (A) indicates the first isolatedstereoisomeric form (B) indicates the second isolated stereoisomericform

TABLE 7

Comp. Ex. Physical No. No. R^(a) R^(b) Data 10 B9 Br —CH(CH₃)₂ mp. 184°C. 12 B11 CH₃ —CH₃ mp. 114° C. 58 B7 CH₃ —CH(CH₃)₂ [(B),(R)]; H₂O (1:1);mp. 60° C.; [α]₂₀ ^(D) (5.20 mg/1 ml in methanol) = −131.15 67 B9 CH₃—CH(CH₃)₂ [(A),(S)]; H₂O (1:1); mp. 91° C.; [α]₂₀ ^(D) (4.50 mg/1 ml inmethanol) = +126.44 68 B9 CH₃ —CH(CH₃)₂ [(A),(R)]; H₂O (1:1); mp. 60°C.; [α]₂₀ ^(D) (5.42 mg/1 ml in methanol) = +62.18 69 B9 Br —CH(CH₃)₂[(A),(S)]; mp. 70° C.; [α]₂₀ ^(D) (4.78 mg/1 ml in methanol) = +133.2670 B9 Br —CH(CH₃)₂ [(A),(R)]; mp. 60° C.; [α]₂₀ ^(D) (5.43 mg/1 ml inmethanol) = +66.85 71 B9 Br —CH(CH₃)₂ [(B),(R)]; H₂O (1:1); mp. 60° C.;[α]₂₀ ^(D) (5.08 mg/1 ml in methanol) = −136.02 72 B9 Br —CH(CH₃)₂[(B),(S)]; [α]₂₀ ^(D) (5.00 mg/1 ml in methanol) = −58.00 73 B9 CH₃—CH(CH₃)₂ [(B),(S)]; H₂O (1:1); mp. 60° C.; [α]₂₀ ^(D) (4.37 mg/1 ml inmethanol) = −60.18 74 B9 CH₃ —CH₃ [(A),(R)]; H₂O (1:1); mp. 70° C.;[α]₂₀ ^(D) (5.00 mg/1 ml in methanol) = +73.00 75 B9 CH₃ —CH₃ [(A),(S)];H₂O (1:1); mp. <50° C.; [α]₂₀ ^(D) (4.60 mg/1 ml in methanol) = +126.5276 B9 CH₃ —CH₃ [(B),(S)]; H₂O (1:1); mp. <50° C.; [α ₂₀ ^(D) (4.69 mg/1ml in methanol) = −57.78 77 B9 CH₃ —CH₃ [(B),(R)]; H₂O (1:2); mp. <50°C.; [α]₂₀ ^(D) (4.74 mg/1 ml in methanol) = −127.64 83 B11 CH₃ —CH(CH₃)₂mp. 110° C. (A) indicates the first isolated stereoisomeric form (B)indicates the second isolated stereoisomeric form

TABLE 8

Comp. Ex. Physical No. No. b R^(a) R^(b) R^(c) R^(d) Data 14 B13 CH CH₃—C₂H₄—O—C₂H₅ H H 84 B13 CH CH₃ —[(CH₂)₂—O]₂—CH₃ H H 85 B13 CH phenyl—C₂H₄—O—C₂H₅ H H 86 B13 CH CH₃ —C₂H₄—O—CH₃ H H 87 B7 CH Br CH₂—CH₃ H CH₃H₂O; mp. 60° C. 88 B13 CH CH₃ —C₂H₄—O—CH₃ Cl CH₃ HCl (1:3)/H₂O (1:3) 89B13 N CH₃ —C₂H₄—O—CH₃ H CH₃

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C1 In Vitro Screening for ActivityAgainst Respiratory Syncytial Virus

The percent protection against cytopathology caused by viruses(antiviral activity or IC₅₀) achieved by tested compounds and theircytotoxicity (CC₅₀) were both calculated from dose-response curves. Theselectivity of the antiviral effect is represented by the selectivityindex (SI), calculated by dividing the CC₅₀ (cytotoxic dose for 50% ofthe cells) by the IC₅₀ (antiviral activity for 50% of the cells).

Automated tetrazolium-based colorimetric assays were used fordetermination of IC₅₀ and CC₅₀ of test compounds. Flat-bottom, 96-wellplastic microtiter trays were filled with 180 μl of Eagle's BasalMedium, supplemented with 5% FCS (0% for FLU) and mM Hepes buffer.Subsequently, stock solutions (7.8× final test concentration) ofcompounds were added in 45 μl volumes to a series of triplicate wells soas to allow simultaneous evaluation of their effects on virus- andmock-infected cells. Five five-fold dilutions were made directly in themicrotiter trays using a robot system. Untreated virus controls, andHeLa cell controls were included in each test. Approximately 100 TCID₅₀of Respiratory Syncytial Virus was added to two of the three rows in avolume of 50 μl. The same volume of medium was added to the third row tomeasure the cytotoxicity of the compounds at the same concentrations asthose used to measure the antiviral activity. After two hours ofincubation, a suspension (4×10⁵ cells/ml) of HeLa cells was added to allwells in a volume of 50 μl. The cultures were incubated at 37° C. in a5% CO₂ atmosphere. Seven days after infection the cytotoxicity and theantiviral activity was examined spectrophotometrically. To each well ofthe microtiter tray, 25 μl of a solution of MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) wasadded. The trays were further incubated at 37° C. for 2 hours, afterwhich the medium was removed from each cup. Solubilization of theformazan crystals was achieved by adding 100 μl 2-propanol. Completedissolution of the formazan crystals were obtained after the trays havebeen placed on a plate shaker for 10 min. Finally, the absorbances wereread in an eight-channel computer-controlled photometer (Multiskan MCC,Flow Laboratories) at two wavelengths (540 and 690 nm). The absorbancemeasured at 690 nm was automatically subtracted from the absorbance at540 nm, so as to eliminate the effects of non-specific absorption.

Particular IC₅₀, CC₅₀ and SI values are listed in Table 9 hereinbelow.

TABLE 9 Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 87 0.00032 10.12 31623 10 0.000637.86 63096 88 0.002 20 10000 67 0.004 63.40 15849 130.0126 >100.08 >7943 58 0.0501 79.41 1585 11 0.1259 9.95 79 801.2589 >99.45 >79

1. A compound of formula

an addition salt or stereochemically isomeric form thereof wherein-a¹=a²-a³=a⁴- represents a bivalent radical of formula—CH═CH—CH═N—  (a-5); wherein each hydrogen atom in the (a-5) mayoptionally be replaced by halo, C₁₋₆alkyl, nitro, amino, hydroxy,C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, carboxyl, aminoC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl, ora radical of formula

wherein -Z is O, CH—C(═O)—NR^(5a)R^(5b), CH₂, CH—C₁₋₆alkyl, N—OH orN—O—C₁₋₆alkyl; Q is a radical of formula

wherein Y¹ is a bivalent radical of formula —NR²— or —CH(NR²R⁴)—; X¹ isNR⁴, S, S(═O), S(═O)₂, O, CH₂, C(═O), C(═CH₂), CH(OH), CH(CH₃),CH(OCH₃), CH(SCH₃), CH(NR^(5a)R^(5b)), CH₂—NR⁴ or NR⁴—CH₂; X² is adirect bond, CH₂, C(═O), NR⁴, C₁₋₄alkyl-NR⁴, NR⁴—C₁₋₄alkyl; u is 2 or 3;v is 2; and whereby each hydrogen atom in the carbocycles and theheterocycles defined in radicals (b-4), (b-5), and (b-6) may optionallybe replaced by R³; with the proviso that when R³ is hydroxy orC₁₋₆alkyloxy, then R³ can not replace a hydrogen atom in the α positionrelative to a nitrogen atom; G is C₁₋₁₀alkanediyl substituted with oneor more hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, C₁₋₆alkylthio,arylC₁₋₆alkylthio, HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— orarylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—; R¹ is a monocyclic heterocycle oraryl; said heterocycle being selected from piperidinyl, piperazinyl,pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,tetrahydrofuranyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl; and each heterocyclemay optionally be substituted with 1 or where possible more substituentsselected from halo, hydroxy, amino, cyano, carboxy, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkyloxy, hydroxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)amino, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, polyhaloC₁₋₆alkyl,C₁₋₆alkylcarbonylamino, C₁₋₆alkyl—SO₂—NR^(5c)—, aryl-SO₂—NR^(5c)—,C₁₋₆alkyloxycarbonyl, —C(═O)—NR^(5c)R^(5d), HO(—CH₂—CH₂—O)_(n)—,halo(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—,arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— and mono- ordi(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n); each n independently is 1, 2, 3 or4; R² is hydrogen, formyl, C₁₋₆alkylcarbonyl, Hetcarbonyl, pyrrolidinyl,piperidinyl, homopiperidinyl, C₃₋₇cycloalkyl substituted with N(R⁶)₂, orC₁₋₁₀alkyl substituted with N(R⁶)₂ and optionally with a second, thirdor fourth substituent selected from amino, hydroxy, C₃₋₇cycloalkyl,C₂₋₅alkanediyl, piperidinyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonylamino, aryl and aryloxy; R³ is hydrogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, arylC₁₋₆alkyl or arylC₁₋₆alkyloxy; R⁴ ishydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl; R^(5a), R^(5b), R^(5c) and R^(5d)each independently are hydrogen or C₁₋₆alkyl; or R^(5a) and R^(5b), orR^(5c) and R^(5d) taken together form a bivalent radical of formula—(CH₂)_(s)— wherein s is 4 or 5; R⁶ is hydrogen, C₁₋₄alkyl, formyl,hydroxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl or C₁₋₆alkyloxycarbonyl; aryl isphenyl or phenyl substituted with 1 or more substituents selected fromhalo, hydroxy, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, andC₁₋₆alkyloxy; and Het is pyridyl, pyrimidinyl, pyrazinyl, orpyridazinyl.
 2. A compound according to claim 1, wherein R¹ is phenyloptionally substituted with halo, C₁₋₆alkyl or C₁₋₄alkyloxy; or pyridyloptionally substituted with 1 or more substituents selected fromarylC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyl, aryl, mono- ordi(C₁₋₆alkyl)amino, C(═O)—NR^(5c)R^(5d), halo or C₁₋₆alkyl.
 3. Acompound according to claim 1, wherein G is C₁₋₄alkanediyl substitutedwith hydroxy, C₁₋₆alkyloxy, HO(—CH₂—CH₂—O)_(n)—,C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)— or arylC₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—.
 4. Acompound according to claim 1, wherein Q is a radical of formula (b-5)wherein v is 2 and Y¹ is —NR²—.
 5. A compound according to claim 1,wherein X¹ is NH or CH₂.
 6. A compound according to claim 1, wherein R²is hydrogen or C₁₋₁₀alkyl substituted with NHR⁶ wherein R⁶ is hydrogenor C₁₋₆alkyloxycarbonyl.
 7. A method of treating a respiratory syncytialviral infection, comprising the step of administering a therapeuticallyeffective amount of a compound of claim
 1. 8. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound ofclaim
 1. 9. A process of preparing a composition as claimed in claim 8,comprising the step of intimately mixing said carrier with saidcompound.
 10. A process of preparing a compound as claimed in claim 1,comprising at least one step selected from the group consisting of: a)reacting an intermediate of formula (II-a) or (II-b) with anintermediate of formula (III)

 with R¹, G, Q and -a¹=a²-a³=a⁴- defined as in claim 1, and W₁ being aleaving group, in the presence of a base and in a reaction-inertsolvent; b) deprotecting an intermediate of formula (IV)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, H-Q₁ being definedas Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, and P being a protective group; c) deprotectingand reducing an intermediate of formula (IV-a)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, H-Q₁ being definedas Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, Q_(1a)(CH═CH) being defined as Q₁ provided thatQ₁ comprises an unsaturated bond, and P being a protective group; d)deprotecting an intermediate of formula (V)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₂ beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen; e) deprotecting an intermediateof formula (VI)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₂ beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen, and P being a protective group;f) deprotecting an intermediate of formula (VII) or (VIII)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, H-Q₁,(OH) beingdefined as Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen and provided that Q comprises a hydroxy moiety,H₂N-Q₂,(OH) being defined as Q according to claim 1 provided that bothR⁶ substituents are hydrogen or R² and R⁴ are both hydrogen and providedthat Q comprises a hydroxy moiety, and P being a protective group; g)amination of an intermediate of formula (IX)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N-Q₃H beingdefined as Q according to claim 1 provided that both R⁶ substituents arehydrogen or R² and R⁴ are both hydrogen, and the carbon adjacent to thenitrogen carrying the R⁶, or R² and R⁴ substituents contains at leastone hydrogen, in the presence of an amination reagent; h) reducing anintermediate of formula (X)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H₂N—CH₂-Q₄being defined as Q according to claim 1 provided that Q comprises a—CH₂—NH₂ moiety, in the presence of a reducing agent; i) reducing anintermediate of formula (X-a)

 with G, and -a¹=a²-a^(3=a) ⁴- defined as in claim 1, H₂N—CH₂-Q₄ beingdefined as Q according to claim 1 provided that Q comprises a —CH₂—NH₂moiety, and R^(1′) being defined as R¹ according to claim 1 providedthat it comprises at least one substituent, in the presence of areducing agent and solvent; j) amination of an intermediate of formula(XI)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, andH₂N—CH₂—CHOH—CH₂-Q₄, being defined as Q according to claim 1 providedthat Q comprises a CH₂—CHOH—CH₂—NH₂ moiety, in the presence of anamination reagent; k) reacting an intermediate of formula (XII) withformic acid, formamide and ammonia

 with R¹, G, and -a¹=a²-a^(3=a) ⁴- defined as in claim 1, and H—C(═O)-Q₁being defined as Q according to claim 1 provided that R² or at least oneR⁶ substituent is formyl; l) amination of an intermediate of formula(XIII) by reaction with an intermediate of formula (XIV)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and R^(2a)—NH—HQ₅being defined as Q according to claim 1 provided that R² is other thanhydrogen and is represented by R^(2a), R⁴ is hydrogen, and the carbonatom adjacent to the nitrogen atom carrying the R² and R⁴ substituents,carries also at least one hydrogen atom, in the presence of a reducingagent; m) reducing an intermediate of formula (XV)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, and(R⁶)₂N—[(C₁₋₉alkyl)CH₂OH]—NH—HQ₅ being defined as Q according to claim 1provided that R² is other than hydrogen and is represented by C₁₋₁₀alkylsubstituted with N(R₆)₂ and with hydroxy, and the carbon atom carryingthe hydroxy, carries also two hydrogen atoms, and provided that R⁴ ishydrogen, and the carbon atom adjacent to the nitrogen atom carrying theR² and R⁴ substituents, carries also at least one hydrogen atom, with areducing agent; n) deprotecting an intermediate of formula (XVI),(XVI-a) or (XVI-b)

 with G, and -a¹=a²-a³=a⁴- defined as in claim 1, and H-Q₁ being definedas Q according to claim 1 provided that R² or at least one R⁶substituent is hydrogen, and R^(1a)-(A-O—H)_(w), R^(1a′)-(A-O—H)₂ andR^(1a″)-(A—O—H)₃ being defined as R¹ according to claim 1 provided thatR¹ is substituted with hydroxy, hydroxyC₁₋₆alkyl, orHO(—CH₂—CH₂—O)_(n)—, with w being an integer from 1 to 4 and P or P₁being a protecting group, with an acid; o) amination of an intermediateof formula (XVII)

 with R¹, G, -a¹=a²-a³=a⁴-, Alk, X¹ R² and R⁴ defined as in claim 1, inthe presence of an amination agent; p) amination of an intermediate offormula (XIX)

 with R¹, G, and -a¹=a²-a³=a⁴- defined as in claim 1, andQ₆N—CH₂—C₁₋₃alkyl-NR⁴ being defined as Q according to claim 1 providedthat in the definition of Q, X² is C₂₋₄alkyl-NR⁴, in the presence of anamination agent; q) deprotecting an intermediate of formula (XXI)

 with R¹, Q, and -a¹=a²-a³=a⁴- defined as in claim 1, and HO-G₁ beingdefined as G according to claim 1 provided that G is substituted withhydroxy or HO—(CH₂CH₂O—)_(n); and r) reducing an intermediate of formula(XXII)

 with R¹, Q, and -a¹=a²-a³=a⁴- defined as in claim 1, and H-G₂-OH beingdefined as G according to claim 1 provided that G is substituted withhydroxy and the carbon atom carrying the hydroxy substituent carriesalso at least one hydrogen, in the presence of a reducing agent.
 11. Theprocess of claim 10, further comprising the step of converting saidcompound of formula (I) into a therapeutically active non-toxic acidaddition salt by treatment with an acid.
 12. The process of claim 10,further comprising the step of converting said compound of formula (I)into a therapeutically active non-toxic base addition salt by treatmentwith alkali.
 13. The process of claim 10, further comprising the step ofconverting the acid addition salt form of compound of formula (I), orstereochemically isomeric forms, thereof, into the free base bytreatment with alkali.
 14. The process of claim 10, further comprisingthe step of converting the base addition salt form of compound offormula (I), or stereochemically isomeric forms, thereof, into the freeacid by treatment with acid.
 15. The process of claim 10, furthercomprising the step of converting said compound of formula (I), orstereochemically isomeric form thereof, into a differentstereochemically isomeric form of said compound of formula (I).